Aminoalkyl secocanthine derivatives and their use

ABSTRACT

A compound of the formula (I) or a pharmaceutically acceptable salt thereof: ##STR1## wherein: R 1  is hydrogen, C 1-6  alkyl, C 1-6  alkoxy or halogen; 
     R 2  and R 3  are both hydrogen or together represent a bond; 
     R 4  is hydrogen and R 5  is hydrogen or R 4  and R 5  together represent an oxo group; 
     R 6  is C 1-7  alkyl substituted by NR 8  R 9  where R 8  and R 9  are independently hydrogen or C 1-4  alkyl or together are C 3-7  polymethylene optionally containing a further hetereoatom which is oxygen, sulphur or nitrogen substituted by R 10  where R 10  is hydrogen, C 1-4  alkyl or benzyl, and optionally substituted by one or two C 1-4  alkyl, C 2-5  alkanoyl, C 1-4  alkoxycarbonyl, aminocarbonyl optionally substituted by one or two C 1-6  alkyl groups or by a benzyl group, cyano, phenyl or benzyl and wherein any phenyl or benzyl group is optionally substituted in the phenyl ring by one or two halo, CF 3 , C 1-4  alkyl, C 1-4  alkoxy, cyano or nitro groups; and 
     R 7  is hydrogen or C 1-4  alkyl.

This invention relates to compounds having pharmacological activity, toa process for their preparation and their use as pharmaceuticals.

J.Am. Chem. Soc. 1981, 103 6990-6992 discloses secocanthine derivativesof formaula (A): ##STR2## wherein Ra is hydrogen or benzyl. Nopharmacological activity is disclosed for these compounds.

EP-0167901-A published on 15th Jan. 1986, discloses a pharmaceuticalcomposition comprising a compound of formula (B) or a pharmaceuticallyacceptable salt thereof: ##STR3## wherein: R_(a) is hydrogen, C₁₋₆alkyl, C₁₋₆ alkoxy or halogen;

R_(b) and R_(c) are both hydrogen or together represent a bond;

R_(d) is hydrogen and R_(e) is hydrogen or R_(d) and R_(e) togetherrepresent an oxo group;

R_(f) is hydrogen; C₁₋₆ alkyl; C₃₋₇ cycloalkyl; C₃₋₇ cycloalykyl-C₁₋₄alkyl; phenyl or phenyl C₁₋₇ alkyl in which the phenyl moiety isoptionally substituted by one or two of halogen, ortho-nitro, meta-orpara-methoxy, methyl or NR_(h) R_(i) wherein R_(h) and R_(i) areindependently hydrogen or C₁₋₆ alkyl or R_(h) R_(i) together are C₂₋₆polymethylene, or 3,4-disubstituted by methylenedioxy or ethylenedioxy;or monocyclic heteroaryl-C₁₋₄ alkyl or aliphatic heterocyclyl-C₁₋₄ alkylof up to six ring atoms, the heteroatom(s) being selected from oxygen,sulphur or nitrogen, any amino nitrogen heteroatom optionally C₁₋₄ alkylsubstituted; and

R_(g) is hydrogen or C₁₋₄ alkyl;

and a pharmaceutically acceptable carrier.

It is disclosed that the compounds have anti-hypoxic activity and/oractivity against cerebral oxygen deficiency and are therefore useful intreating cerebrovascular disorders and disorders associated withcerebral senility.

A further group of secocanthine derivatives have now been discovered tohave anti-ischaemic activity, in particular anti-hypoxic activity and/oractivity against cerebral oxygen deficiency.

Accordingly, the present invention provides a compound of formula (I) ora pharmaceutically acceptable salt thereof: ##STR4## wherein: R₁ ishydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or halogen;

R₂ and R₃ are both hydrogen or together represent a bond;

R₄ is hydrogen and R₅ is hydrogen or R₄ and R₅ together represent an oxogroup;

R₆ is C₁₋₇ alkyl substituted by NR₈ R₉ where R₈ and R₉ are independentlyhydrogen or C₁₋₄ alkyl or together are C₃₋₇ polymethylene optionallycontaining a further hetereoatom which is oxygen, sulphur or nitrogensubstituted by R₁₀ where R₁₀ is hydrogen, C₁₋₄ alkyl or benzyl, andoptionally substituted by one or two C₁₋₄ alkyl, C₂₋₅ alkanoyl, C₁₋₄alkoxycarbonyl, aminocarbonyl optionally substituted by one or two C₁₋₆alkyl groups or by a benzyl group, cyano, phenyl or benzyl and whereinany phenyl or benzyl group is optionally substituted in the phenyl ringby one or two halo, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or nitro groups;and

R₇ is hydrogen or C₁₋₄ alkyl.

The compounds of the present invention have anti-ischaemic activity, inparticular anti-hypoxic activity and/or activity against cerebral oxygendeficiency and are therefore useful in treating cerebrovasculardisorders and disorders associated with cerebral senility.

Suitable examples of R₁ include hydrogen, methyl, ethyl, n- andiso-propyl, n-, sec-, iso- and tert-butyl, methoxy, ethoxy, fluoro andchloro. R₁ is preferably hydrogen or methyl, most preferably hydrogen.

R₂ and R₃ preferably together represent a bond. R₄ and R₅ are preferablyboth hydrogen.

R₆ is preferably C₃₋₇ alkyl, such as C₄₋₆ or C₅₋₇ alkyl, substituted byNR₈ R₉ where R₈ and R₉ are as defined above. Suitable alkylene chainlengths in R₆ include C₃, C₄ and C₅.

When NR₈ R₉ is a cyclic moiety, it preferably comprises 5 to 7 ringatoms, more preferably 5 or 6 ring atoms.

Suitable examples of cyclic aminoalkyl R₆ include NR₈ R₉ C₁₋₇ alkylwhere R₈ and R₉ together form a piperidine, pyrrolidine, piperazine ormorpholine ring. Suitable examples of optional substituents on cyclicamino C₁₋₇ alkyl R₆ include one or two C₁₋₄ alkyl groups such as methyl,ethyl, n- and iso-propyl, and n-, sec-, iso- and t-butyl.

Suitable examples of acyclic amino alkyl R₆ include C₁₋₄ alkyl aminoC₁₋₇ alkyl and di-C₁₋₄ alkylamino C₁₋₇ alkyl, such as methylamino-,ethylamino-, n- or iso-propylamino-, iso-propylamino-, iso-butylamino-,dimethylamino-, diethylamino, di-n- or iso-propylamino-anddi-iso-butylamino C₁₋₇ alkyl.

Suitable examples of R₇ include hydrogen, methyl, ethyl, n- andiso-propyl, n-, sec-, iso- and tert-butyl. R₇ is preferably hydrogen.

The compounds of formula (I) can form acid addition salts with acids,such as the conventional pharmaceutically acceptable acids, for examplehydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic,citric, lactic, mandelic, tartaric, oxalic and methanesulphonic.

There is a favourable group of compounds within formula (I) of formula(II): ##STR5## wherein R₁,R₂,R₃,R₄,R₅ and R₇ are as defined in formula(I) and R₆ ¹ is NR₈ ¹ R₉ ¹ C₁₋₇ alkyl where R₈ ¹ and R₉ ¹ together areC₃₋₇ polymethylene optionally containing a further heteroatom as definedabove for R₈ and R₉ and optionally substituted by one or two C₁₋₄ alkylgroups. Suitable and preferred values for R₁, R₂, R₃, R₄, R₅, R₆ ¹, R₇,R₈ ¹ and R₉ ¹ are as described under formula (I) for R₁, R₂, R₃, R₄, R₅,R₆, R₇, R₈ and R₉.

There is a sub-group of compounds within formula (II) of formula (IIa):##STR6## wherein R₁, R₂, R₃, R₆ ¹ and R₇ are as defined in formula (II).

Suitable and preferred values for the variables are as described for thecorresponding variables under formula (I). There is a sub-group ofcompounds within formula (IIa) of formula (IIb): ##STR7## wherein R₁,R₂, R₃ and R₇ are as defined in formula (I) and R₆ ² is(1-piperidyl)C₁₋₇ alkyl substituted by one or two C₁₋₄ alkyl groups.

Suitable and preferred values for the variables are as described for thecorresponding variables under formula (I).

There is another sub-group of compounds within formula (IIa) of formula(IIc): ##STR8## wherein R₁, R₂, R₃, and R₇ are as defined in formula (I)and R₆ ³ is --(CH₂)₅ NR₈ ¹ R₉ ¹ where R₈ ¹ and R₉ ¹ are as defined informula (II).

Preferably R₁ is hydrogen.

Preferably R₂ and R₃ represent a bond.

Preferably R₆ ² or R₆ ³ is 5-(3,5dimethyl-1-piperidyl) pentyl

Preferably R₇ is hydrogen.

There is a further group of compounds within formula (II) of formula(IId): ##STR9## wherein R₆ ¹ is as defined in formula (II) and theremaining variables are as defined in formula (I).

Suitable and preferred values for R₆ ¹ and R₇ are as described underformulae (II) and (IIa).

Another subgroup of compounds within formula (I) is of formula (III):##STR10## wherein R₁, R₂, R₃, R₄, R₅, and R₇ are as defined in formula(I) and R₆ ⁴ is NR₈ ² R₉ ² C₁₋₇ alkyl where R₈ ² and R₉ ² areindependently hydrogen or C₁₋₄ alkyl.

Suitable and preferred values for the variables are as described underformula (I).

Preferably R₁ is hydrogen.

Preferably R₂ and R₃ represent a bond.

Preferably R₄ and R₅ are both hydrogen.

Preferably R₆ ⁴ is --(CH₂)₅ NR₈ ² R₉ ² where R₈ ² and R₉ ² are asdefined.

Preferably R₇ is hydrogen.

Where compounds of formula (I) can exist in more than one stereoisomericform, the invention extends to each of these forms and to mixturesthereof.

The invention further provides a process for the preparation of acompound of formula (I), or a pharmaceutically acceptable salt thereof,which process comprises the conversion of a compound of formula (V).##STR11## wherein R₁, R₄ and R₅ are as defined in formula (I) and Y is agroup convertible to CH₂ NR₆ 'R₇ ' where R₆ ' is R₆ as defined informula (I) or a group convertible thereto and R₇ ' is an aminoprotecting group or R₇ as defined in formula (I), into a compound offormula (Va): ##STR12## and thereafter, optionally and as necessary,converting R₆ ' when other than R₆ into R₆, removing any R₇ ' aminoprotecting group, interconverting R₆ and/or R₇ to other R₆ or R₇,reducing the R₂ /R₃ bond and/or, when R₄ /R₅ is oxo, reducing the oxogroup to give a compound wherein R₄ and R₅ are both hydrogen and/orforming a pharmaceutically acceptable salt.

Y may be conventional amine precursor. Suitable examples include CN, COQwhere Q is H or a leaving group such as halo, C₁₋₄ alkoxy or carboxylicacyloxy, and CH₂ L where L is CON₃, N₃, NO₂ or X where X is a leavinggroup such as hydroxy, halo, C₁₋₄ alkoxy, C₁₋₄ alkanoyloxy, C₁₋₄alkoxycarbonyloxy, tosyloxy or mesyloxy.

The reaction converting the compound of formula (V) into that of formula(Va) may be carried out under the conventional conditions appropriate tothe particular group Y in formula (V).

Thus, when Y is CH₂ CON₃, the conversion is a Curtius degradationcarried out conventionally, by heating in dry inert solvent, such asbenzene, and then subsequent hydrolysis of the thus formed isocyanateunder acid conditions.

When Y is CN, the conversion is a reduction to the primary amine, forexample with a reducing agent such as diborane or LiAlH₄ at elevatedtemperature and in an inert solvent such as tetrahydrofuran, or withhydrogen over Raney nickel in the presence of ammonia at ambienttemperature in a polar solvent such as methanol.

When Y is CHO, the conversion is a condensation with hydroxylaminefollowed by reduction of the thus formed oxime over a metallic catalyst,or is a reductive amination with a primary or secondary amine using areducing agent such as NaBH₃ CN in a polar solvent such as CH₂ Cl₂ /CH₃OH at elevated temperature.

Alternatively the intermediate imine may be prepared in a non polarsolvent such as benzene in the presence of an acid catalyst e.g.p-toluenesulphonic acid and reduced with a reducing agent such as NaBH₄.

When Y is COQ where Q is a leaving group, the conversion is anucleophilic substitution by ammonia or a primary or secondary amineunder conventional conditions appropriate for leaving group Q, followedby reduction of the resulting amide with e.g. LiAlH₄ in an inert solventsuch as tetrahydrofuran at elevated temperature followed by work up. Forexample, when Q is halo such as chloro, the nucleophilic substitutionmay be carried out at ambient or lower temperature in the presence of anacid acceptor such as triethylamine in a polar solvent such as CH₂ Cl₂,followed by work up to give the amide which may be reduced as justdescribed.

When Y is CH₂ N₃, the conversion is a reduction of the azide to theprimary amine with e.g. hydrogen over a metallic catalyst.

When Y is CH₂ NO₂, the conversion is a reduction of the nitro group tothe primary amine with a reducing agent such as LiAlH₄, or hydrogen overRaney nickel or Pd/C catalyst in a polar solvent such as ethanol.

When Y is CH₂ X, the conversion is a nucleophilic substitution byammonia or a primary or secondary amine or azide ion, under conventionalconditions appropriate for the leaving group X. Thus, when X is hydroxy,it is first converted into a good leaving group such as mesylate ortosylate (using mesyl or tosyl chloride respectively) or chloride (usingSOCl₃). The nucleophilic substitution may be carried out at elevatedtemperature in a polar solvent such as acetonitrile in the presence ofan acid acceptor such as diisopropyl ethylamine. Alternatively, theleaving group may be substituted by nitrile to yield a compound offormula (V) where Y═CH₂ CN. Hydrolysis and conversion by conventionalmethods yields a compound where Y═CH₂ CON₃ via the acid as describedhereinafter.

Suitable examples of R₆ ' convertible to R₆ include hydrogen or an aminoprotecting group.

In the resulting compound of formula (Va) in the case where R₆ ' or R₇ 'is an amino protecting group such as C₁₋₆ alkoxy carbonyl,aryloxycarbonyl, C₁₋₆ alkanoyl or phenyl C₁₋₇ alkanoyl, the protectinggroup may be removed by conventional procedures.

The conversion of any R₆ ' amino protecting group to R₆ via the R₆ 'hydrogen intermediate, the conversion of R₆ ' hydrogen to R₆, or theinterconversion of an R₇ hydrogen atom may be carried out byconventional amine alkylation such as simple alkylation or, morepreferably, by acylation followed by reduction of the amide, or byreductive alkylation.

Acylation may be carried out using the appropriate acyl chloride oranhydride and the subsequent reduction of the resulting amide withLiAlH₄ in the presence of AlCl₃.

The reductive alkylation procedure is preferably carried out by heatingwith the aldehyde or ketone in an organic acid, such as acetic acid,then reducing the product in situ using an alkaline borohydride such assodium borohydride or cyanoborohydride. The reaction can also be carriedout in an alcohol, in which case the reduction can be carried out eitherchemically, for example with a borane such as trimethylammoniumborane oran alkaline borohydride or with hydrogen in the presence of a catalystsuch as Raney nickel.

It is also possible to use an aprotic solvent, for example an aromaticsolvent such as benzene or toluene, the water formed being eliminatedeither at room temperature by means of a drying-agent or under refluxheating of the solvent by means of a Dean-Stark water-separator; thereduction can then be expediently carried out with hydrogen in thepresence of a catalyst such as palladiated carbon or platinum oxide.These methods may be subject to certain limitations, depending on thenature of the aldehyde or ketone used.

It is also possible to use a more universal method. For example, the R₆'/R₇ hydrogen compound and the aldehyde or ketone to be condensed aredissolved in a mixture of solvents which can advantageously be amethanol-dichloromethane mixture in the presence of a complex reducingagent such as quaternary ammonium cyanoborohydride or, more simply, analkaline cyanoborohydride solubilised by a phase-transfer agent, forexample sodium cyanoborohydride and aliquat 336(Cf. Hutchins, R. O. andMarkowitz, M., Journal of Organic Chemistry 1981, 46, pp.3571-3574).

The alkylation, acylation or reductive alkylation may introduce therequired moiety NR₈ R₉ in the alkyl substituted R₆ directly, oralternatively by way of an amine precursor Y¹ which is convertible toCH₂ NR₈ ' R₉ ' (where R₈ ' and R₉ ' are R₈ and R₉ or groups convertiblethereto) analogously to the conversion of the group Y in the compound offormula (V). For example, the amine precursor Y¹ may be of the formulaCH₂ X¹ where X¹ is a leaving group as defined for X above, such as haloe.g chloro which can be subsequently displaced by a compound HNR₈ R₉.Where the alkylation reaction is of the acylation/reduction type,reduction of the amide described above may be carried out before orafter this displacement.

Accordingly, the invention further provides a process for thepreparation of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof which process comprises the conversion of acompound of the formula (Vb): ##STR13## to a compound of formula (Vc):##STR14## in which R₆ " is C₁₋₆ alkyl substituted by a group Y¹ where Y¹is a group convertible to CH₂ NR₈ ' R₉ ' or C₁₋₆ alkanoyl substituted byCH₂ NR₈ R₉ or Y¹ as defined, where R₈ ' and R₉ ' are R₈ and R₉ or groupsconvertible thereto, and R₁, R₂, R₃, R₄ and R₅ are as defined in formula(I), the conversion being followed by, or simultaneously with,optionally or as necessary, the reduction of R₆ " alkanoyl to R₆ "alkyl, the conversion of Y¹ to CH₂ NR₈ 'R₉ ', the conversion of R₈ ' andR₉ ' to R₈ and R₉, the reduction of the R₄ /R₅ oxo group, the reductionof the R₂ /R₃ double bond, and/or the formation of a pharmaceuticallyacceptable salt.

The conversion may be carried out as described above for the conversionof an R₆ ', or interconversion of an R₇, hydrogen atom.

The invention provides intermediates of the formula (Vc).

The invention also provides intermediates of the formula (Vd): ##STR15##wherein R₆ "' is C₁₋₇ alkanoyl substituted by NR₈ R₉ as defined informula (I) and the remaining variables are as defined in formula (I).

Suitable and preferred values for the variables in formulae (Vc) and(Vd) are as described for the corresponding variables under formula (I).

The reduction of the R₂ /R₃ bond may be carried out conventionally bythe use of an alkaline borohydride in a polar aprotic solvent such asdimethylsulphoxide or by nitromethane in the presence of a strongorganic acid such as methanesulphonic acid or in pure trifluoroaceticacid. Alternatively the bond may be reduced catalytically with hydrogenover platinum oxide catalyst in a solvent permitting protonation of theindolic nitrogen, such as ethanol containing fluoroboric acid or aceticacid containing trifluoroacetic acid.

When R₄ and R₅ together form an oxo group, compounds wherein R₄ and R₅are both hydrogen may be prepared by reduction of the R₄ /R₅ oxo groupformula (I) using a mixed hydride complexed with a Lewis acid, forexample, the complex lithium aluminium hydride-aluminium chloride in aninert solvent such as diethyl ether. When an R₆ or R₇ group other thanhydrogen is introduced initially by acylation to give the amide,simultaneous reduction of the R₄ /R₅ oxo group and the amide moiety maybe effected by appropriate choice of reducing agent, for example themixed hydride complexed with a Lewis acid just described.

When R₂ and R₃ together form a bond and R₄ and R₅ together form an oxogroup, simultaneous reduction of the double bond and the oxo group maybe effected by the use of an alkaline borohydride as described above forthe reduction of an R₂ /R₃ bond.

It will be appreciated that these conversions may take place in anydesired or necessary order.

Pharmaceutically acceptable salts of the compounds of formula (I) may beformed conventionally by reaction with the appropriate acid such asdescribed above under formula (I).

Compounds of formula (V) in which Y is CH₂ CON₃ may be prepared by theformation of the acid chloride followed by reaction of azide ion on anacid of formula (VI): ##STR16## This method is described in J. Am. Chem.Soc. 1981, 103, 6990-6992.

Acids of formula (VI) are known or may be prepared by conventionalmethods. For example, a phenylhydrazine is condensed with 4-oxoazelaicacid (ref. Von Pechmann et. al. Berichte 1904, 37, p 3816). Thehydrazone thus obtained is subjected to a Fischer cyclisation to givethe acid of formula (VI).

Compounds of formula (V) in which R₄ and R₅ are both hydrogen may beprepared by the reaction of a compound of formula (VII). ##STR17## with(i) ClCOCOR₁₁, where R₁₁ is alkoxy such as ethoxy or halo such aschloro, followed by reduction with LiAlH₄ to give a compound of formula(V) where Y is --CH₂ OH which may subsequently be reacted with azide ionto give the corresponding compound where Y is --CH₂ N₃ ;

(ii) CH₂ ═CH--R₁₂, where R₁₂ is a 1-carbonyl containing group or cyano,under basic conditions, followed by hydrolysis and reaction on theresulting acid group by azide ion as described above, to give a compoundof formula (V) where Y is --CH₂ CON₃ ;

(iii) formaldehyde in the presence of dimethylamine followed by reactionof cyanide ion on the resulting tertiary amine, if necessary afterquaternization, to give a compound of formula (V) where Y is --CN;

(iv) CH₂ ═CHNO₂ under basic conditions to give a compound of formula (V)where Y is CH₂ NO₂.

Compounds of formula (VII) can be prepared according to Hans Zimmer, J.Heterocylic Chemistry 21, 623(1984).

Compounds of formula (V) in which Y is CHO may be prepared from thecorresponding compound in which Y is CN by a variety conventionalprocedures such as, for example, reaction with diisobutylaluminiumhydride.

Compounds of formula (V) in which Y is COQ where Q is a leaving groupmay be prepared from the corresponding compound in which Y is CN by, forexample, hydrolysis under acid conditions of the nitrile to give thecorresponding acid, followed by conversion of the hydroxyl group to aleaving group Q such as chloro with a chlorinating agent such as oxalylchloride. Interconversion of leaving groups Q may be carried outconventionally.

Compounds of formula (V) in which R₄ and R₅ are both hydrogen and Y is--CH₂ CN, may alternatively be prepared by homologation of a compound offormula (VIII): ##STR18## prepared according to D. N. Reinhoudt et al.,Tetrahedron Letters 26 (5) 1985, 685-8. The nitrile is first reduced tothe amine which is quaternised and reacted with cyanide ion to give therelevant compound of formula (V).

In the formulae (VI), (VII) and (VIII) above, R₁ is as defined informula (I).

The invention further provides a pharmaceutical composition comprising acompound of formula (I), including pharmaceutically acceptable saltsthereof, and a pharmaceutically acceptable carrier.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, suppositories, reconstitutable powders, or liquidpreparations such as oral or sterile parenteral solutions orsuspensions.

In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulphate.

The solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of, for example, emulsions,syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (whichmay include edible oils), for example almond oil, fractionated coconutoil, oily esters such as esters of glycerine, propylene glycol, or ethylalcohol; preservatives, for example methyl or propyl p-hydroxybenzoateor sorbic acid; and if desired conventional flavouring or colouringagents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, and, depending on theconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending on the method ofadministration.

The invention also provides a method of treatment of cerebrovasculardisorders and/or disorders associated with cerebral senility in mammalsincluding humans, which comprises administering to the sufferer aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

The dose of the compound used in the treatment of such disorders willvary in the usual way with the seriousness of the disorders, the weightof the sufferer, and the relative efficacy of the compound. However, asa general guide suitable unit doses may be 0.05 to 100 mg. for example0.2 to 50 mg; and such unit doses may be administered more than once aday, for example two or three times a day, so that the total dailydosage is in the range of about 0.1 to 100 mg/kg; and such therapy mayextend for a number of weeks or months.

At the above indicated dosage range, no adverse toxicological effectsare indicated for the compounds of the invention.

In a further aspect the invention provides a compound of formula (I) foruse as an active therapeutic substance.

The invention further provides a compound of formula (I), includingpharmaceutically acceptable salts thereof, for use in the treatment ofcerebrovascular disorders and/or disorders associated with cerebralsenility.

The following examples illustrate the invention and the followingdescriptions illustrate the preparation of intermediates thereto.

DESCRIPTION 1 6-Oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-10-propionicacid. (D1) ##STR19##

This compound has been described by Y. Ban in J. Amer. Chem. Soc. 1981,103 (23), pp.6990-6992. Melting-point 163°-165° C.

IR (KBr)ν=3200-2500; 1700; 755 cm⁻¹.

DESCRIPTION 2 6-Oxo-10-(2-aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole hydrochloride (D2) ##STR20##

(a) Acid chloride: 1.5 g oxalyl chloride (11.5 mmoles) and 1 drop of DMFwere added dropwise to a suspension of 1.5 g (5 mmoles) of the acid ofDescription 1 in 4 ml benzene. When the liberation of vapours sloweddown the mixture was heated for 30 minutes at 60°-70° C. The brownsolution thus obtained was concentrated to dryness in vacuo, leaving aresidue of maroon-coloured cyrstals, which were used as they were forstage (b).

(b) Acyl axide: The crude acid chloride from stage (a) was dissolved in12 ml dry acetone and added dropwise to an ice-cooled solution of 0.4 gsodium azide in 1 ml water and stirred for a further 30 minutes at 6°C., then for 30 minutes at room temperature. The mixture was thendiluted with 25 ml water, the precipitate formed was filtered off,washed with water and then dried in vacuo at room temperature, givingthe corresponding acyl azide as a white crystalline solid.

(c) 56.3 mmoles crude azide from stage (b) was dissolved in 70 mldrybenzene and heated under reflux for 40 minutes. There was asubstantial liberation of nitrogen and the solution turned black. 100 mlbenzene and 24 ml concentrated HCl were then added and heated underreflux for 1 hour. There was a substantial liberation of gas/vapours,and then a precipitate was formed. The solution was then concentrated todryness, giving the crude amine hydrochloride. Recrystallisation in a4/1 mixture of ethanol/water produced a white crystalline solid D2described by Y. Ban(ref.cited) of m.pt. 330°-335° C. (decomposition). IR(KBr) ν=3200-2400; 1700; 745 cm⁻¹. UV (ethanlo)λmax=243; 267; 292; 302nm.

DESCRIPTION 36-Oxo-10-(2-(5-chlorovaleryl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole(D3) ##STR21##

A solution of 15 g 5-chlorovaleric acid chloride in 100 ml CHC1₃ wasadded to an ice-cooled solution of 25 g D2 and 30 g triethylamine in 300ml dry CHCl₃.

After addition of the acid chloride the mixture was left to stand for 2hours at room temperature, then twice shaken with a 10 percent solutionof citric acid and once with brine. After drying and evaporation theresidue was crystallized from ethyl acetate. 24 g amide D3 wereobtained, m.pt 98° C.

DESCRIPTION 4 6-Oxo-10-(2-(5-(3,5-dimethylpiperidyl-(1))valeryl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2 (D4)##STR22##

17.4 g D3 and 1.7 g 3,5-dimethylpiperidine were heated in 100 ml DMF at60° C. for 16 hours.

After addition of 500 ml water and extraction with ethyl acetate theorganic phase was dried and evaporated. the residue was crystallisedfrom di-isopropylether to give D4. Yield: 14.7 g. M.pt: 135°-6° C.

DESDRIPTION 5 10-(2-Aminoethyl-6,7,8,9-tetrahydropyrido[1,2-a]indolehydrochloride (5) ##STR23##

Compound D5 is described in EP-O 167901-A as Example 19 on page 45.

DESCRIPTION 610-(2-(5-Chlorovaleryl)aminoethyl)-6,7,8,9-tetrahydropyrido [1,2a]indole (D6) ##STR24##

43 g (0.2 mole) Amine D5 were dissolved in 300 ml CHCl₃ and 0.5 moletriethylamine. A solution of 0.3 mol 5-chlorovaleric acid chloride wasadded at 0°-5° C. and the solution left to stand for 4 hours at roomtemperature, then twice shaken with a 10 percent solution of citric acidand sodium carbonate, respectively. After drying and evaporation, theresidue was crystallised from ethyl acetate to yield 56 g D6.

Mpt: 93° C.

DESCRIPTION 710-(2-(5-(3,5-Dimethyl-piperidyl-(1))valeryl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a] indole (D7) ##STR25##

8 g D6, 5.7 g 3,5-dimethylpiperidine, 5.1 g diisopropylethylamine and1.5 g KI in 100 ml DMF were heated at 80° C. for 20 hours. Afterdilution with 500 ml water and extraction with ethyl acetate the organicphase was extracted 3 times with 100 ml 1N HCl solution, the aqueousphase made alkaline with sodium hydroxide solution and extracted withether. The ether solution was dried, evaporated and the residuecrystallized from diisopropyl ether to yield 4.4 g D7.

Mpt. 123° C.

NMR (CDCl₃) δ=6.9-7.6 [4]m; 5.8 [1] tr broad (exchange); 4.0 [2] tr J=6Hz; 3.5 [2] q (after exchange tr); 0.8 [6] tr J=6 Hz.

DESCRIPTION 8 to 10

The following compounds were prepared analogously:

10-(2-(5-Dimethylaminovaleryl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a] indole (D8)

10-(2-(5-(Pyrrolidinyl-(1))valeryl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a] indole (D9)

10-(2-(5-(Morpholinyl-(1))valeryl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a] indole (D10)

10-(2-(5-(Piperidyl-(1))valeryl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2,-a] indole (D11) ##STR26##

Compounds D8 and D10 were obtained as yellow oils and used in thefollowing examples without further purification.

Compound D9:

Mpt: 81° C.

NMR (CDCl₃) δ=7.0-7.7 [4] m; 5.75 [1] s broad exchange; 4.0 [2] tr J=6Hz; 3.48 [2] q J=6 Hz (after exchange tr J=6 Hz); 3.9 [4] tr.

Compound D11:

Mpt: 183°-184° C. (hydrochloride)

NMR (DMSO d₆): δ=10.62 [1] s (exchange); 8.02 [1] tr. J=5.4 Hz; 7.6-6.95[4] m; 4.02 [2] tr. J=5.7 Hz; 3.55-2.65 [12] m; 2.3-1.25 [16] m.

EXAMPLE 110-(2-(5-(3,5Dimethylpiperidyl-(1)pentyl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2,-a]indole(E ##STR27## Method A:

5 g D4 was reduced with a mixture of 2.3 g LiAlH₄ and 6.7 g AlCl₃ in 250ml ether and 250 ml THF. After working up, the base was crystallised bythe addition of an ethanolic solution of fumaric acid. 2.4 g Fumarate ofEl were obtained.

Mpt: 110°-111° C.

NMR (DMSO d₆) δ=0.85 [6] d J=6 Hz; 4[2] tr J=7 Hz; 5.5-6.4[2.5] exch.;6.6[3] s; 6.9-7.6[4]m.

Method B:

4.4 g D7 were dissolved in 50 ml THF and dropped into a boilingsuspension of 3 g LiAlH₄ in 50 ml THF. After 3.5 h of reflux the excessof LiAlH₄ was destroyed by addition of water, the precipitate wasfiltered off, washed with CH₂ Cl₂ and the filtrate evaporated. Theresidue was chromatographed on SiO₂ and the pure polar isomer of E1(seems to be trans dimethyl) was isolated as the dihydrochloride byaddition of ethanol/HCl.

Mpt: 231° C.

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        (1/2H.sub.2 O)                                                                        calc.    65.39  9.18     8.79 14.84                                           found:   65.49  9.18     8.63 14.45                                   ______________________________________                                    

NMR (DMSO d₆) δ=10.8 [1] s broad (exchange); 9.3 [2] s broad (exchange);6.9-7.7 [4] m; 4.0 [2] tr J=6 Hz; 0.88 [6] d

EXAMPLE 210-(2-(5-Dimethylaminopentyl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2a-]indole (E2) ##STR28##

10 g D8 oil was dissolved in 50 ml THF, added to a suspension of 3 gLiAlH₄ in 100 ml THF and refluxed for 25 h. Work up as described for E1Method B. The product was isolated as the dihydrochloride.

Mpt: 250° C.

    ______________________________________                                                 C    H           N      Cl                                           ______________________________________                                        calc.      62.99  8.81        10.49                                                                              17.71                                      found:     62.61  8.68        10.55                                                                              16.98                                      ______________________________________                                    

NMR (DMSO d₆) δ=11 [1] s broad (exchange); 9.6 [2] s broad (exchange);6.9-7.7 [4] m; 4 [2] tr J=6 Hz; 2.7 [6] s

EXAMPLE 310-(2-(5-(Piperidyl-(1))pentyl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (E3) ##STR29##

Compound E3 was prepared analogously to compound E2, from 3.5 g D11using 2 g LiAlH4 and a 12 h reflux. Mpt:238° C. (dihydrochloride)

NMR (DMSO d₆): δ=10.6 [1] s (exchange); 9.35 [2] s (exchange);7.67-6.9[4] m; 4.0[2] tr. J=5.5 Hz; 3.6-2.6[14] m; 2.2-1.2[16[ m.

EXAMPLE 410-(2-(5-(Pyrrolidyl-(1))pentyl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (E4) ##STR30##

Compound E4 was prepared analogously to compound E2, from 6.5 g D9 using3 g LiAlH₄ and a 4 h reflux

Mpt: (dihydrochloride) 255°-6° C.

    ______________________________________                                                   C    H          N      Cl                                          ______________________________________                                        (1/2H.sub.2 O)                                                                        calc.    63.44  8.70     9.65 16.28                                           found:   63.17  8.64     9.62 16.09                                   ______________________________________                                    

NMR (DMSO d₆) δ=9.85 [3] s broad (exchange); 6.9-7.3 [3] m; 7.7 [1] m; 4[2] tr J=6 Hz.

EXAMPLE 510(2-(5-(Morpholinyl-(1))pentyl)aminoethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole (E5) ##STR31##

Compound E5 was prepared analgously to compound E2, from 9.7 g D10 oilusing 4 g LiAlH₄ and a 2 h reflux.

Mpt: 252°-3° C.

    ______________________________________                                                         C    H                                                       ______________________________________                                        (1/2H.sub.2 O)                                                                          calc.        61.19  8.48                                                      found:       60.83  8.43                                            ______________________________________                                    

NMR (DMSO d₆) δ=11.4 [1] s broad (exchange); 9.3 [2] s broad (exchange);7.0-7.7 [4] m; 3.7-4.2 [6] m; 1.2-2.3 [10] m.

PHARMACOLOGICAL DATA Triethyltin-induced cerebral oedema in the rat.

The cerebral oedema is induced by oral administrations repeated for 5consecutive days-one administration per day-of triethyltin chloride at adose of 2 mg/kg. The study substances are also administered orally twicedaily as aqueous solution or suspension at a dose of 1 ml/100 gbody-weight; these administrations are given during the 5 days ofintoxication with tin. Three groups of 6 male specific pathogen-free(SPF) Wistar rats of 280±10 g body-weight are used for each compoundstudied:

1 control group

1 group intoxicated with triethyltin

1 group intoxicated with triethyltin and treated with the studiedcompound.

The rats are killed on the evening of the fifth day; the brain isremoved, weighed fresh and after desiccation to constant weight and thewater content of each brain is calculated:

[H₂ O]=fresh weight-dry weight.

The following are then calculated:

the mean water content (M±Sm%) of each group;

the protection index P due to the administered compound: ##EQU1##

The results are given in Table 1.

                  TABLE 1                                                         ______________________________________                                                                  EFFECT (P)                                                                             SIG-                                       COMPOUND  n     DOSAGE    % reduction                                                                            NIFICANCE*                                 ______________________________________                                        E1 (Method A)                                                                           6     2 × 50.0                                                                          65       0.01                                       E2        6     2 × 12.5                                                                          59       0.01                                       ______________________________________                                         *unpaired Wilcoxon signed rank test                                           n = number of animals.                                                   

Toxicity

No toxic effects were observed in the above tests.

We claim:
 1. A compound of formula (I) or a pharmaceutially acceptablesalt thereof: ##STR32## wherein: R₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxyor halogen;R₂ and R₃ are both hydrogen or together represent a bond; R₄is hydrogen and R₅ is hydrogen or R₄ and R₅ together represent an oxogroup; R₆ is C₁₋₇ alkyl substituted by NR₈ R₉ where R₈ and R₉ togetherare C₃₋₇ polymethylene optionally containing a further hetereoatom whichis oxygen, sulphur or nitrogen substituted by R₁₀ where R₁₀ is hydrogen,C₁₋₄ alkyl or benzyl, and said C₃₋₇ polymethylene being optionallysubstituted by one or two C₁₋₄ alkyl, C₂₋₅ alkanoyl, C₁₋₄alkoxycarbonyl, aminocarbonyl optionally substituted by one or two C₁₋₆alkyl groups or by a benzyl group, cyano, phenyl or benzyl and whereinany phenyl or benzyl group is optionally substituted in the phenyl ringby one or two halo, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano or nitro groups;and R₇ is hydrogen or C₁₋₄ alkyl.
 2. A compound according to claim 1 offormula (II): ##STR33## wherein R₁,R₂,R₃,R₄,R₅ and R₇ are as defined inclaim 1 and R₆ ¹ is NR₈ ¹ R₉ ¹ C₁₋₇ alkyl where R₈ ¹ and R₉ ¹ togetherare C₃₋₇ polymethylene optionally containing a further heteroatom asdefined above for R₈ and R₉ and optionally substituted by one or twoC₁₋₄ alkyl groups.
 3. A compound according to claim 2 wherein R₆ is--(CH₂)₅ NR₈ ² R₉ ¹ in which R₈ ¹ and R₉ ¹ are as defined in claim
 2. 4.A compound according to claim 1 wherein R₁ is hydrogen.
 5. A compoundaccording to claim 1 wherein R₂ and R₃ together represent a bond.
 6. Acompound according to claim 1 wherein R₄ and R₅ are both hydrogen.
 7. Acompound according to claim 1 wherein R₇ is hydrogen. 8.10-(2-(3,5-Dimethylpiperidyl-(1))pentyl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole,10`-(2-(5-piperidyl-(1))pentyl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole,10-(2-(5-(pyrrolidyl-(1))pentyl)aminoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole,10-(2-(5-(morpholinyl-(1))pentyl)aminoethyl-6,7,8,9-tetrahydropyrido[1,2-a]indoleora pharmaceutically acceptable salt of any of the foregoing.